6beta, 19beta-oxido-3, 5-cyclosteroid compounds and process for preparing the same



United States Patent O e cnam. (cines-239.55)

This invention relates to 6,19-oxido-3,5-cyclo-steroid compounds having the general formula a et' wherein R is a member selected from the group consisting of keto group (IO), O-lower aliphatic acyl group containing 2 to 4 carbon atoms such as O-ocetyl, O-propionyl or O-butyryl, acetyl group and group, and it further relates a process for preparing these compounds.

The 6,8,l9,6-oxido-3,5-cyclosteroid compounds having the above mentioned Formula i produced by the process according t-o the present invention are novel compounds unknown in the prior arts and useful as intermediates for the preparation of various l9norsteroid compounds possessing potent physiological activities. For example, 6,6, l9-oxido-3,5-cyclo-5ct-androstan-17-one can be converted to a known compound, 19-nor-androst-4-ene-3,17-dione by heating the former in an aqueous solvent, such as 90% aqueous acetone, containing a mineral acid such as sulfurie acid to forfm 3,6,19 dihydroxyandrost-S-en-17-one, successively subjecting the latter to oxidation with iones reagent, to hydrolysis with alkali and then to oxidation with Jones reagent to for-m 10-carboxy-estra-S-ene317- di-one and treating the latter with a mineral acid such as hydrochloric acid or alkali to form 19-nor-,aadrost-4-ene- 3,17-dione, which is known to be an important intermedidate for physiologically active 19-nor-steroid compounds. Alternatively, 6,8,19-oxido-3,5cyclo5-androstan-17one can be converted to a known compound, estro- (10)-ene- 3,17-dione yby reacting the former with acetic acid and Lewis acid such as borone-trifiuoride etherate to form 3,8,l9-dihydroxy `androst-S-en-17-one 3-acetate, oxidizing the latter with i ones reagent to form 3hydroxyestra5 en-17-onel0carboxylic acid 3-acetate, subjecting the latter to pyrolysis to form 3acetoxyestra5(10)-en-17-one, lij-.f'drolyzing the latter with alkali to form -hydroxyestra- 5 (10)-cn-17-one and oxidizing the latter with Jones reagent to form estra-5(10)-ene-3,17dione, which is known to oe an important intermediate for physiologically active t-nor-steroid compounds.

It is an object of this invention to provide new steroid compounds, 6,3,l9/-oxido-3,5-cyclosteroid compounds having the above Formula I useful las intermediates for the preparation of various 19-nor-steroid compounds possessing potent physiological activities `and a process for preparing these compounds.

According to the present invention, the above-mentioned 3,338,124 Patented June 11, 1968 6,3,19/3-oxido-3,5-cyclosteroid compounds may be produced by treating -hydroxy-S,5-cyclosteroid compounds having the general formula wherein R has the same meaning as above with lead tetracetate in an inert water-immiscible organic solvent.

Examples of the inert water-immiscible organic solvents used in the process according to the present invention include benzene, toluene, carbon tetrachloride, cyclohexane and hexane. It is preferable to carry out the reaction at a temperature between about 70 C. and about 110 C. under moisture-free conditions `for about 2 to 24 hour-s. It has been found advantageous that the reaction is effccted in the presence of ya catalytic amount of a substance capable of producing free-radical such as benzoyl peroxide.

After completion of the reaction, the reaction product is isolated from the reaction mixture by one of the conventional procedures. For example, after completion of the reaction, the reaction mixture is filtered, the filtrate 39 is successively washed with potassium iodide solution, so-

dium thiosulfate solution and then water, the organic layer is separated from the aqueous layer, the organic layer separated is distilled and the residue is subjected to chromatography.

Examples of 6-hydroxy3,5-cyclosteroid compounds used as the starting material are Gti-hydroxy-3,5-cyclo-5aandrostan-l7-one. Compound I 6,l7-dihydroxy-3,5cy Aclo-5ot-androstane-l7-acetate, Compound Il 6hydroxy3, S-cyclo-Sa-pregnan-Znone, Compound lil and -hyroxy-3,5-cyclo-5a-cholestane, Compound IV. Literature references to the preparation of these compounds are as follows: Compound l: A. Butenandt; L. A. Sturdnyi; Ber. 75 591 (1942); Compound Il: This compound is prepared by treating the 3,17,5dihydroxy androst-S-one 17-acetate of P, Wieland, n. Mascha; Hav. Chim. Acta, 32 176s (1949) with tosyl chloride, then treating the resultant compound with potassium acetate in aqueous acetone; Compound III: D. K. Patel, V. Petrow, I. A. Stuart- Webb, .l.C.S., 1957, 665; Compound IV: E. M. Kosower, S. Winstein, I.A.C.S., 78, 4347 (1956). Examples of 6,8, 19-oxido3,S-cyclosteroid compounds obtained by the process according to the present invention are 6;3,19oxido 3,5-cyclo-5a-androstan-l7-one, 6,8,19-oxido-3,5cyclo5a androstan 17ol 17-acetate, 6i?,19-oxido3,5cyclo5a a pregnan-ZO-one and 6p,19-oxido-3,5-cyclo-5ot-cholestane.

Examples of this invention will be illustrated below. However, it is to be understood that the following examples are given for illustration but not for limitation of the scope of thi-s invention.

EXAMPLE 1 To a solution of 1.0 g. of 6-hydroxy-3,5cyclo5a androstan-17-one in 50 ml. of benzene are added 2.0 g. of lead tetracetate and the resulting mixture is retiuxed under moisturefree conditions for 20 hours. After completion of the reaction, the reaction mixture is cooled and liltered over Celite to remove lead diacetate formed during the reaction. The filtrate is successively washed o with 5% potassium iodide solution, water, 5%, so-

dium thiosulfate solution and water. After drying of the iiltrate over sodium sulfate, the filtrate is distilled to remove the organic solvent. The residue is a pale yellow, syrupy substance. The residue is dissolved in a mixture of benzene and n-hexane (1:4) and the solution is passed through a column of alumina (Woelm, grade III). First elution with a mixture of benzene and n-hexane (1:4) gives 366 mg. of a substance melting at 126 to 128 C. which is recrystallized from n-hexane to give 6;?,19-oxide-3,5-cyclo-5a-androstan 17 one as needles having a melting point of 136 to 138 C.

Subsequent elution with benzene gives `480 mg. of the starting lmaterial having a melting of 128 to 130 C. which is recrystallized from n-hexane to give ra crystal- -line material melting at 136 to 138 C. The yield of the desired product on the .basis of the starting material except the recovered one is about 70% EXAMPLE 2 To a solution of 10 g. of 6-hydroxy3,5cyclo5a pregnan-ZO-one in `500 ml. of benzene are added 20 g. of lead tetracetate and 1.0 g. of benzoyl peroxide and the mixture is retiuxed under moisture-free conditions for 15 hours. After completion of the reaction, the reaction mixture is cooled and filtered over Celite to remove lead diacetate formed during the reaction. The filtrate is successively washed with 5% potassium iodide solution, water,5% sodium thiosulfate solution and water. The filtrate is dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue is dissolved in a mixture of benzene and n-hexane (2:1) and the solution is chromatographed on alumina (Woelm, grade Ill). Elution with a 4mixture of benzene and n-hexane gives 1.56 g. of a substance having -a melting point of 165 to 175 C. which is recrystallized from hexane to yield 6,19-oxido-3,5-cyc1o5pregnan20-one as prisms melting at 173 to 175 C.

Analysis.-Calcd for C21H3002: C, 80.21%; H, 9.62%. Found: C, 79.56%; H, 9.42%.

EXAMPLE 3 To a solution of 10 g. of 6-hydroxy3,5cyclo5a androstan-17-one in 500 ml. of benzene are added 20 g. of lead tetracetate and 1.0 g. of benzoyl peroxide and the mixture is retluxed under moisture-free conditions for hours. After completion of the reaction, the reaction -mixture is cooled and filtered over Celite to remove lead diacetate formed during the reaction. The filtrate is successively washed with 5% potassium iodide solution, water, 5% sodium thiosulfate solution and water. The filtrate is dried over anhydrous sodium sulfate and distilled 4to remove the solvent. The residue, which is a pale yellow syrupy substance, is dissolved in a mixture of benzene and n-hexane (1:2) and the solution is passed through -a column of alumina (Woelm, grade III). First elution with a mixture of benzene and n-hexane (1:2) gives 3.59 g. of a substance melting at 131134 C. which is recrystallized from n-hexane to yield 65,19-oxido-3,S-cyclo-Sa-androstan-17-one as needles having a melting point of 136 to 138 C. Subsequent elution with benzene gives 3.5 g. of the starting material melting at 134 to 136 C.

EXAMPLE 4 To a solution of 10 g. of 6-hydroxy-3,5cyclo5 cholestane in 500 ml. of benzene are added 20 g. of lead tetracetate and 1.0 g. of benzoyl peroxide and the mixture is relinxed under moisture-free conditions for 18.5 hours. After completion of the reaction, the reaction mixture is cooled and filtered over Celite to remove lead diacetate formed during the reaction. The tiltrate is successively Washed with 5% potassium iodide, water, 5% sodium thiosulfate solution and then water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue is dissolved in a mixture of benzene and n-hexane (1:4) and the solution is passed through a column of alumina (Woelm, grade Ill). First elution with a mixture of benzene and n-hexane (1:3) gives 3.6 g. of substance having melting point of -81" C. which is recrystallized from acetone Ito yield 66,19-oxido- 3,5-cyclo-5u-cholestane as needles melting at 81 to 82 C.

Analysis- Calau for CMHMO: C, 84.32%; H, 11.53%. Found: C, 83.99%;H, 11.46%.

Subsequent elution with the same eluant is 4.2 g. of the starting material.

EXAMPLE 5 To a solution of 1.350 g. of 6u,19oxido3,5cyclo5a andr0stan-17-one in 135 ml. of glacial acetic acid is added 20 drops of BF3-etherate and the mixture is allowed to stand a-t room temperature for 8.5 hours. Water is-added to the reaction mixture and the mixture is extracted with ethyl ether. The extract is washed with sodium bicarbonate solution, dried and distilled to remove the ethyl ether. The residue is chromatographed on Woelm alumina of grade HI. Elution with benzene gives 1.397 g. of 3,l9-dihydroxyandrost-5-en-17-one 3-'acetate melting at 161 C.

EXAMPLE 6 To a solution of 1.18 g. of 3,8,19 dihydroxyandrost- 5 en 17 one 3 acetate in 120 ml. of acetone is added 3 ml. of Jones reagent (a solution prepared by dissolving 26.72 g. of chromic anhydride in 23 ml. of concd. sulfuric acid andl diluting the solution with water to a total volume of ml.) in nitrogen atmosphere at a temperature of 18 C. and the mixture is stirred. After 5 minutes, an additional amount of 1.8 ml. of Jones reagent is added to the mixture and the mixture is stirred at the same temperature for an additional 7 minutes. After completion of the reaction, 1 ml. of methanol is added to the reaction mixture and the mixture is distilled under reduced pressure to remove most of the solvent. Water is added to the residue and the mixture is extracted with ethyl ether. The extract is shaken with 5% sodium bicarbonate solution and aqueous layer is separated from organic layer. The aqueous layer is made acidic by dilute hydrochloric acid and the acidified aqueous layer is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. There is obtained the desired product as white crystalline substance. Recrystallization of the white crystalline substance from a mixture of acetone and ethyl ether gives 318 hydroxyestra 5 en 17 one- 10 carboxylic acid 3 acetate having melting point of 253 C. l(with decomposition).

Avzalyss.-Calcd for C21H28O5; C. 69.97% H, 7.83%. Found: C, 69.81%; I-I, 7.92%.

EXAMPLE 7 In a 50 ml. round-bottomed ask immersed .in an oil bath maintained at a Itemperature of 260 to 270 C., 120 mg. of 3ft hydroxyestra 5 en 17 one 10,8 carboxylic acid 3 acetate obtained in Example 6 is placed under nitrogen, atmosphere, whereby the molten content is subjected to pyrolysis with decarboxylation. After a period of 10| minutes, the decomposed product is cooled and extracted with ethyl ether. Distillation of the ethyl ether from the extract gives a syrupy substance. The syrupy substance is dissolved in a mixture of benzene and n hexane (1 :1). The solution is passed through a column of alumina (Woelm, grade III). Elution with a mixture of benzene and n hexane (1:1), evaporation of the solvent from the eluate and recrystallization of the residue thus obtained from aqueous acetone give 3,8 acetoxyestra5(10)en17one melting at 76.5 to 77.5 C.

Analysz's.-Calcd for C20H28O3: C, 75.91%; H, 8.92%. Found: C, 75.85%; H, 8.71%.

EXAMPLE s A solution of 3,8 acetoxyestra 5 (10) en 17 one in ml. of 2% methanolic potassium hydroxide solution is heated under reflux for 1.5 hours. After completion of the reaction, Water is added to the reaction mixture and the mixture is extracted with ethyl ether. The extract is washed with Water, dried and distilled to remove the ethyl ether. Addition of a small amount of hexane to the syrupy substance gives a crystalline substance which is recrystallized from hexane to yield 3-hydroxyestra5(10) en-17-one as crystalline substance melting at 131 to 132 C.

Arzalysz'S.-Calcd for C18H25O2Z C, 8.79%; H, 9.55%. Found: C, 79.13%; H, 9.41%.

EXAMPLE 9 To a solution of 40 mg. of 3hydroxyestra5(10)-en 17 one in 5 ml. of acetone is added 0.05 ml. of Jones reagent under nitrogen atmosphere with stirring and the mixture is stirred. After a period of 3 minutes, 0.5 ml. of methanol is added to the reaction mixture and the mixture is extracted with ethyl ether. The extract is Washed with water, dried over anhydrous sodium sulfate and distilled to remove the ethyl ether. The residual syrupy substance is recrystallized from ethyl ether to yield estra- 5(10)ene3.17dione melting at 148 C.

We claim:

1. A compound having the general formula wherein R is a member selected from the group consisting of keto group (=O), O-lower aliphatic acyl group containing 2 to 4 carbon atoms, acetyl group and group.

10 2. A compound of the formula References Cited UNITED STATES PATENTS 3,001,989 9/1961 Ringold et al. 260-239.55 3,008,957 11/1961 Ringold et al 260-239.55 3,033,862 5/ 1962 Ringold et al. 260-239.55 3,036,068 5/1962 Ringold et al 260-239.55 3,065,228 11/ 1962 Bowers 260--239.55 3,067,198 12/1962 Wettstcin et al. 260-239.55

LEWIS GOTTS, Primary Examiner.

H. A. FRENCH, Assistant Examiner. 

1. A COMPOUND HAVING THE GENERAL FORMULA 